Using proteomics to uncover extracellular matrix interactions during cardiac remodeling

Abstract

The left ventricle (LV) responds to a myocardial infarction with an orchestrated sequence of events that result in fundamental changes to both the structure and function of the myocardium. This collection of responses is termed as LV remodeling. Myocardial ischemia resulting in necrosis is the initiating event that culminates in the formation of an extracellular matrix (ECM) rich infarct scar that replaces necrotic myocytes. While the cardiomyocyte is the major cell type that responds to ischemia, infiltrating leukocytes and cardiac fibroblasts coordinate the subsequent wound healing response. The matrix metalloproteinase family of enzymes regulates the inflammatory and ECM responses that modulate scar formation. Matridomics is the proteomic evaluation focused on ECM, while degradomics is the proteomic evaluation of proteases as well as their inhibitors and substrates. This review will summarize the use of proteomics to better understand matrix metalloproteinase roles in post myocardial infarction LV remodeling.

Keywords: Degradomics; Matridomics; Matrix metalloproteinases; Myocardial infarction.

Figure 1

A representative speckle tracking-based strain echocardiographic analysis of the left ventricle (LV) pre- and post-myocardial infarction (MI). A: Baseline and B: Day 7 post-MI. The post-MI image illustrates LV dilation, reduced ejection faction, and decreased radial and longitudinal strains. Images were acquired with a Vevo 2100 (Visualsonics; our own unpublished data). Analysis was conducted using the VevoStrain™ software.

Figure 2

A representative experimental design for a matridomics study. Two strategies typically used to identify ECM proteins differentially expressed are: 1) decellularization of the tissue to focus in on the extracellular matrix environment; or 2) SILAC labeling to examine the fibroblast secretome. SILAC- stable isotope labeling by amino acids in cell culture; ECM- extracellular matrix; ELISA- enzyme-linked immunosorbent assay; LV- left ventricle; and TIMP- tissue inhibitor of metalloproteinases.

Figure 3

A selection of the MMP-9 molecular interaction network. Known substrates are shown in the black boxes, while candidate substrates are shown in the white boxes. Factors that bind to MMP-9, but are not substrates, are shown in gray. IL-8- interleukin-8; SPARC- secreted protein acidic and rich in cysteine; TFPI- tissue factor pathway inhibitor; PF 4- platelet factor 4; IL-1β- interleukin-1β; ICAM-1- intercellular adhesion molecule-1; OPN- osteopontin; GRO α- growth related oncogene alpha; FGF R1- fibroblast growth factor receptor 1; ET-1- endothelin-1; and NGAL- neutrophil gelatinase-associated lipocalin.